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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] The role of the proto-oncogene ETS2 in acutemegakaryocytic leukemia biology and therapy.

Acutemyeloid leukemia (AML) in Down syndrome (DS) children has several unique features including a predominance of the acutemegakaryocytic leukemia (AMkL) phenotype, higher event-free survivals compared to non-DS children using cytosine arabinoside (ara-C)/anthracycline-based protocols and a uniform presence of somatic mutations in the X-linked transcription factor gene, GATA1.

Several chromosome 21-localized transcription factor oncogenes including ETS2 may contribute to the unique features of DS AMkL.

In a doxycycline-inducible erythroleukemia cell line, K562pTet-on/ETS2, induction of ETS2 resulted in an erythroid to megakaryocytic phenotypic switch independent of GATA1 levels.

Microarray analysis of doxycycline-induced and doxycycline-uninduced cells revealed an upregulation by ETS2 of cytokines (for example, interleukin 1 and CSF2) and transcription factors (for example, TAL1), which are key regulators of megakaryocytic differentiation.

These results suggest that ETS2 expression is linked to the biology of AMkL in both DS and non-DS children, and that ETS2 acts by regulating expression of hematopoietic lineage and transcription factor genes involved in erythropoiesis and megakaryopoiesis, and in chemotherapy sensitivities.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in acuteleukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in acuteleukemias; however, the molecular mechanisms remain unclear.

The median level of RUNX1b transcripts in Down syndrome (DS) children with acutemegakaryocytic leukemia (AMkL) were 4.4-fold (P < .001) lower than that in non-DS AMkL cases.

Anderson Cancer Center between 1987 and 2003 and compared them with 1800 patients with non-M7, non-M3 AML treated during the same period.

The median age of the M7 AML group was 56 years (range, 21-78 years); 22 patients (59%) had an antecedent hematologic disorder or myelodysplastic syndrome or both, and 7 patients (19%) had previously received chemotherapy for other malignancies.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Hematopoietic stem cell transplantation for de novo acutemegakaryocytic leukemia in first complete remission: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT).

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Down syndrome (DS) persons are born with various hematopoietic abnormalities, ranging from relatively benign, such as neutrophilia and macrocytosis, to a more severe transient myeloproliferative disorder (TMD).

However, sometimes the TMD represents a premalignant disease that develops into acutemegakaryocytic leukemia (AMKL), usually in association with acquired GATA1 mutations.

Despite these defects, the Ts1Cje mice do not develop disease resembling either TMD or AMKL, and this was not altered by a loss of function allele of Gata1.

Thus, loss of Gata1 and partial trisomy of chromosome 21 orthologs, when combined, do not appear to be sufficient to induce TMD or AMKL-like phenotypes in mice.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Congenital transient leukemia: a case report].

[Transliterated title] Un cas de leucémie congénitale transitoire.

Neonates with Down's syndrome have an increased risk for congenital leukaemia, particularly acute megakaryoblastic leukaemia (FAB, M7) which most often resolves spontaneously and is called transient leukaemia.

OBSERVATION: We report a transient leukaemia with an isolated pericardial effusion in a phenotypically normal neonate.

DISCUSSION: Congenital leukaemias, with trisomy 21 on blasts cells have a good prognosis that justifies observation before using chemotherapy.

[Title] GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acutemegakaryocytic leukemia.

Somatic mutations in the GATA1 transcription factor have been detected exclusively and almost uniformly in Down syndrome AMkL patients, suggesting a potential linkage to the chemotherapy sensitivity of Down syndrome megakaryoblasts.

Stable transfection of wild-type GATA1 cDNA into the Down syndrome AMkL cell line CMK resulted in decreased (8- to 17-fold) ara-C sensitivity and a threefold-lower generation of the active ara-C metabolite ara-CTP compared with that for mock-transfected CMK cells.

These results suggest that GATA1 transcriptionally upregulates cytidine deaminase and that the presence or absence of GATA1 mutations in AML blasts likely confers differences in ara-C sensitivities due to effects on cytidine deaminase gene expression, which, in turn, contributes to the high cure rate of Down syndrome AMkL patients.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Children with Down syndrome (DS) have a unique form of acutemegakaryocytic leukemia (AMKL) characterized by the presence of mutations in the GATA1 gene leading to increased chemosensitivity and a favorable outcome.

We describe an 8-month-old male with DS who was diagnosed with AMKL without a mutation in the GATA1 gene.

The patient was treated according to the DS-AML-regimen but his disease progressed and he succumbed 9 months later.

This rare case of DS AMKL without a GATA1 mutation with an unfavorable outcome suggests that GATA1 testing may play a useful role in initial stratification.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Arsenic trioxide (ATO) induces apoptosis in a range of solid tumors and leukemia cells, and has been clinically applied for the treatment of acute promyelocytic leukemia with confirmed efficacy.

Acutemegakaryocytic leukemia (AMKL) is an aggressive malignancy with poor prognosis, if bone marrow transplantation is not possible.

In this study, we applied flow cytometry, Western blot analysis and microarray techniques to investigate the effects of ATO on apoptosis and the cell division cycle of AMKL cell lines CHRF-288-11 and MEG-01.

Our data demonstrated that ATO is a potent agent against AMKL as indicated by apoptotic markers, Annexin V and caspase-3.

ATO induced delays of cell cycle progression at S phase and arrest at G2/M phase of AMKL cells, but caspase-3 expression appeared not to be phase-specific.

The multiple-signaling mechanism of ATO warrants it a potential agent to incorporate in the treatment regimen of AMKL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Acute megakaryoblasticleukemia (AML M7) is a biologically heterogeneous form of acutemyeloid leukemia accounting for 14.6% of cases.

In many instances in the past, AML M7 has been classified as undifferentiated leukemia, myelodysplasia, myelofibrosis or some other disease because of its complex clinical presentation or the difficulty of obtaining and interpreting bone marrow samples.

However, with currently available morphological, cytochemical, cytogenetic and immunophenotypic methods, AML M7 can now be reliably diagnosed.

Although the radiographic spectrum of bony changes in leukemia have been well characterized, skeletal X-ray abnormalities in the setting of AML M7 in pediatric patients have been described in few reports that were associated with bone marrow fibrosis.

Here we report on a 14-month-old girl who presented with a massive periosteal reaction of the extremities and clavicles associated with myelofibrosis, a presenting feature of AML M7.

The results indicated that the two cases were diagnosed primarily as acute lymphocytic leukemia (common cell subtype) and acutemegakaryocytic leukemia, in which chromosome abnormalities or activation of protooncogene in leukemic cells were observed.

The complete hematopuietie reconstitution of donor origin was obtained in these 2 cases after HLA HBMT, but the leukemic cells in these 2 leukemia patients were confirmed to be donor origin after relapse, their blood groups and HLA genotype were found to be originated from donor.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Acutemegakaryocytic leukemia is a rare form of acute myelogenous leukemia and may occur either de novo or by transformation of a preexisting myelodysplastic or myeloproliferative process including blast crisis of chronic myeloid leukemia (CML).

Megakaryocytic blast crisis as the presenting manifestation of CML is extremely rare.

We describe such a patient with no prior hematologic disease who presented with acute megakaryoblasticleukemia and extramedullary involvement, in whom the leukemic cells carried the BCR-ABL1 translocation as part of a complex karyotype.

Using targeted sequential fluorescence in situ hybridization (T-FISH) technique, we detected two copies of BCR-ABL1 fusion gene in the leukemic blasts while the neutrophils carried a single copy of BCR-ABL1 fusion gene, thereby proving the origin of the megakaryoblasticleukemia from a previously undiagnosed CML clone.

Blast crisis as a presenting manifestation of CML is rare and detecting clonal evolution of acuteleukemia by specialized cytogenetic techniques may have important diagnostic and therapeutic implications.

[Chemical-registry-number] EC 2.7.10.2 / Fusion Proteins, bcr-abl

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Molecular insights into Down syndrome-associated leukemia.

PURPOSE OF REVIEW: Four years ago it was discovered that nearly all cases of transient myeloproliferative disorder and acutemegakaryocytic leukemia in children with Down syndrome acquire mutations in the hematopoietic transcription factor gene GATA1.

In addition, multiple studies have shown that GATA1s can substitute for GATA1 in many aspects of megakaryocytic maturation.

Finally, an important clinical study has revealed that GATA1 mutations alone are insufficient for leukemia.

SUMMARY: Leukemia in children with Down syndrome requires at least three cooperating events--trisomy 21, a GATA1 mutation, and a third, as yet undefined, genetic alteration.

Future experiments with human patient samples and mouse models will likely increase our awareness of the role of trisomy 21 in transient myeloproliferative disorder and acutemegakaryocytic leukemia.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Therapy-related acutemyeloid leukemias arise as a result of cytotoxic chemotherapy and/or radiation therapy.

The most common types of acutemyeloid leukemia arising in this setting are acutemyeloid leukemia with maturation, and lesser numbers of acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, or acutemegakaryocytic leukemia.

We present a patient with multiple myeloma who was treated with melphalan and 4 years later developed acute erythroid leukemia.

The morphologic diagnosis of pure erythroid leukemia developing in the setting of multiple myeloma may be challenging.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

JAK3 mutations have been reported in transient myeloproliferative disorder (TMD) as well as in acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL).

To further understand how JAK3 mutations are involved in the development and/or progression of leukaemia in Down syndrome, additional TMD patients and the DS-AMKL cell line MGS were screened for JAK3 mutations, and we examined whether each JAK3 mutation is an activating mutation.

These results suggest that the JAK3 activating mutation is an early event during leukaemogenesis in Down syndrome, and they provide proof-of-principle evidence that JAK3 inhibitors would have therapeutic effects on TMD and DS-AMKL patients carrying activating JAK3 mutations.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The transient myeloproliferative disorder and acutemegakaryocytic leukemia associated with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown.

Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(17(16))65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion.

Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(17(16))65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title]Acute panmyelosis with myelofibrosis: an entity distinct from acute megakaryoblasticleukemia.

The WHO criteria for diagnosing acute panmyelosis with myelofibrosis are somewhat distinct from those for acute megakaryoblasticleukemia.

To determine the potential importance of bone marrow biopsy supplemented by immunohistochemistry in distinguishing between these two conditions, we studied 17 bone marrow biopsies of well-characterized cases of acute panmyelosis with myelofibrosis (six cases) and acute megakaryoblasticleukemia (11 cases).

We compared blast frequency, reticulin content, CD34 expression, and the degree of megakaryocytic differentiation of the blast cells in these two conditions.

Acute panmyelosis with myelofibrosis is characterized by a multilineage myeloid proliferation with a less numerous population of blasts than acute megakaryoblasticleukemia (P<0.01).

In the former condition, blasts are always positive with CD34, while in acute megakaryoblasticleukemia they express CD34 in 60% of the cases.

The blasts in acute panmyelosis with myelofibrosis only rarely express megakaryocytic antigens.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Long-term results of an ultra low-dose cytarabine-based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome.

Children with acute megakaryoblastic leukaemia (AMKL) and Down syndrome (DS) show a favourable response to chemotherapy, probably due to increased sensitivity of the leukaemic blasts to cytarabine.

The survival of children with AMKL and DS was retrospectively compared following treatment with a low-dose chemotherapy protocol, consisting of cytarabine (10 mg/m2/dose), retinylpalmitate and vincristine or standard chemotherapy.

Further reduction of treatment intensity in AMKL of children with DS, therefore, appears feasible.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Unique clinical and biological features of leukemia in Down syndrome children.

Acuteleukemias in children with Down syndrome (DS) are characterized by unique clinical and biological features.

Notable among DS children with acutemyeloid leukemia (AML), is the high frequency of the acutemegakaryocytic leukemia (AMkL) subtype, which uniformly harbor somatic mutations in the transcription factor GATA1 gene.

DS patients with AML, and in particular AMkL, have event-free survival rates of 80-100% in contrast to event-free survival rates of less than 35% for non-DS children with AMkL.

DS children with acute lymphoblastic leukemia have a more heterogeneous disease, with approximately 30% of the patients having somatic JAK2 mutations, heightened methotrexate sensitivity and higher rates of treatment-related toxicities.

These features highlight a striking relationship between genes localized to chromosome 21, leukemogenesis and sensitivity to leukemia chemotherapy agents.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Children with Down syndrome (DS) with acutemegakaryocytic leukemia (AMkL) have very high survival rates compared with non-DS AMkL patients.

Somatic mutations identified in the X-linked transcription factor gene, GATA1, in essentially all DS AMkL cases result in the synthesis of a shorter (40 kDa) protein (GATA1s) with altered transactivation activity and may lead to altered expression of GATA1 target genes.

Our results demonstrate that genes that account for differences in survival between DS and non-DS AMkL cases may be identified by microarray analysis and that differential gene expression may reflect relative transactivation capacities of the GATA1s and full-length GATA1 proteins.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Transient myeloproliferative disorder (TMD) is a hematologic abnormality usually associated with Down syndrome that may present with a skin eruption in addition to typical systemic findings.

Mutations of the globin transcription factor 1 gene, GATA1, are associated with both TMD and acutemegakaryocytic leukemia.

Transient myeloproliferative disorder typically presents with pancytopenia, hepatosplenomegaly, and immature circulating white blood cells, and affects approximately 10% of neonates with Down syndrome.

However, 20% to 30% of neonates with Down syndrome and TMD later develop leukemia.

We report an illustrative case to alert clinicians about this uncommon cause of vesiculopustular eruption in a neonate without the phenotypic characteristics of Down syndrome and review the clinical findings and laboratory studies that aid in accurate diagnosis.

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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Mutations of GATA1, FLT3, MLL-partial tandem duplication, NRAS, and RUNX1 genes are not found in a 7-year-old Down syndrome patient with acutemyeloid leukemia (FAB-M2) having a good prognosis.

The prognosis of leukemia developed in Down syndrome (DS) patients has improved markedly.

Most DS leukemia occurs before 3 years of age and is classified as acutemegakaryocytic leukemia (AMKL).

Mutations in the GATA1 gene have been found in almost all DS patients with AMKL.

In contrast, it has been shown that occurrence of DS acutemyeloid leukemia (DS-AML) after 3 years of age may indicate a higher risk for a poor prognosis, but its frequency is very low.

We here describe the case of a 7-year-old DS boy with AML-M2, who had no history of transient abnormal myelopoiesis or any clinical poor prognostic factors, such as high white blood cell counts or extramedullary infiltration.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title]Acute megakaryoblasticleukemia and loss of the RUNX1 gene.

Since the RUNX1 gene contributes to megakaryopoiesis and acquired trisomy 21 is the most frequent numerical chromosome anomaly in acute megakaryoblasticleukemia (AMLK), a systematic study of RUNX1 abnormalities was performed by fluorescence in situ hybridization in AMLK patients.

PROCEDURE: Children without Down syndrome or acute promyelocytic leukemia who were newly diagnosed with primary myelodysplastic syndrome or acutemyeloid leukemia (AML) M6 or M7 were compared to children with de novo AML M0-M5.

All three groups had significantly inferior overall survival (OS) (P < 0.001) and event free survival (P < 0.001) compared with the 748 children diagnosed with AML FAB M0-M5 when assessed from entry on study.

However, when assessed from successful completion of induction therapy, the 5-year OS (P = 0.090)(49.1 vs. 56.9%) and disease-free survival (DFS) (P = 0.113)(38.0 vs. 46.3%) therapy were not significantly different from other children with AML.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Acute megakaryoblastic leukaemia (AMKL), a relatively rare type of acutemyeloidleukaemia, is characterized by frequent involvement of the liver, spleen and lymph nodes in addition to myelofibrosis in children.

Diagnosis is difficult both clinically and pathologically, and the hepatic or lymph node involvement is not uncommonly misinterpreted as solid tumour.

We report the imaging findings of upper abdominal involvement by AMKL in an infant.

With the association of splenic lesion and lymphadenopathy, the imaging findings were considered indicative of a haematological disorder.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A novel fusion of RBM6 to CSF1R in acute megakaryoblasticleukemia.

Activated tyrosine kinases have been frequently implicated in the pathogenesis of cancer, including acutemyeloid leukemia (AML), and are validated targets for therapeutic intervention with small-molecule kinase inhibitors.

This method revealed the presence of an activated colony-stimulating factor 1 receptor (CSF1R) kinase in the acute megakaryoblasticleukemia (AMKL) cell line MKPL-1.

Expression of the RBM6-CSF1R fusion protein conferred interleukin-3 (IL-3)-independent growth in BaF3 cells, and induces a myeloid proliferative disease (MPD) with features of megakaryoblasticleukemia in a murine transplant model.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblasticleukemia.

Although physicians have known for many decades that children with Down syndrome are predisposed to developing transient myeloproliferative disorder (TMD) and acute megakaryoblasticleukemia (AMKL), many questions regarding these disorders remain unresolved.

First, what is the relationship between TMD and AMKL?

Finally, what factors lead to the increased predisposition to these myeloid disorders?

In this review I will summarize important new insights into the biology of TMD and AMKL gained from the recent discovery that GATA1, a gene that encodes an essential hematopoietic transcription factor, is mutated in the leukemic blasts from nearly all patients with these malignancies.

In addition, I will discuss whether assaying for the presence of a GATA1 mutation can aid in the diagnosis of these and related megakaryoblasticleukemias.

Future research aimed at defining the activity of mutant GATA-1 protein and identifying interacting factors encoded by chromosome 21 will likely lead to an even greater understanding of this intriguing leukemia.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title]Acute megakaryoblasticleukemia in a German Shepherd dog.

Based on microscopic and immunophenotypic findings, a diagnosis of acute megakaryoblasticleukemia (AMegL) was made.

To our knowledge, this is the first report of AMegL in a domestic animal in which immunophenotyping by flow cytometry and a panel of antibodies against CD41/61, CD61, and CD62P were used to support the diagnosis.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Herein, we describe a 16-month-old boy with acute megakaryoblasticleukemia and severe intractable gastrointestinal bleeding controlled by rFVIIa. rFVIIa should be considered as a novel treatment alternative in severe bleeding conditions including leukemias that may have hemostatic defects and platelet dysfunction.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Physical association of the patient-specific GATA1 mutants with RUNX1 in acute megakaryoblasticleukemia accompanying Down syndrome.

Mutations of the GATA1 gene on chromosome X have been found in almost all cases of transient myeloproliferative disorder and acute megakaryoblasticleukemia (AMKL) accompanying Down syndrome (DS).

It has been suggested that loss of the N-terminal portion of GATA1 might interfere with physiological interactions with the critical megakaryocytic transcription factor RUNX1, and this would imply that GATA1s is not able to interact properly with RUNX1.

All of the patient-specific GATA1 mutants interacted efficiently with RUNX1 and retained their ability to act synergistically with RUNX1 on the megakaryocytic GP1balpha promoter, whereas the levels of transcriptional activities were diverse among the mutants.

Thus, our data indicate that physical interaction and synergy between GATA1 and RUNX1 are retained in DS-AMKL, although it is still possible that increased RUNX1 activity plays a role in the development of leukemia in DS.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title]Acute megakaryoblasticleukemia with erythrophagocytosis and thrombosis in a dog.

A 7-year-old, intact male Dachshund was presented to the Lyon veterinary school for lethargy and anorexia of several weeks duration.

Blood smear evaluation and cytologic examination of lymph node and bone marrow aspirate specimens revealed a large population of poorly differentiated blast cells with morphologic features suggesting megakaryocytic lineage.

This case confirms the usefulness of immunochemistry, including for factor XIII, in the diagnosis of megakaryoblasticleukemia, and demonstrates the unique features of tumor cell erythrophagocytosis and marked fibrinous thrombosis, which have not been reported previously in dogs.

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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Twenty-five cases of B-cell precursor acute lymphoblastic leukaemia (ALL) from Down syndrome (DS) patients were analyzed using array comparative genomic hybridization (aCGH) and compared with two other subgroups of non-DS patients with ALL; five cases with high-hyperdiploidy (HH) and nine cases with ETV6-RUNX1 positive clones.

This overall analysis supports the suggestion that, although constitutional trisomy 21 predisposes to ALL/AMKL, the cytogenetic changes associated with DS-ALL in particular, are most similar to those found in non-DS ETV6-RUNX1 positive ALL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The strong association of diagnostic karyotype with clinical outcome has made cytogenetics one of the most valuable diagnostic and prognostic tools for acutemyeloid leukemia (AML).

The subtype M7 is a rare disease of the megakaryoblastic lineage and is mostly associated with complex abnormal karyotype.

We describe the clinical, morphologic, immunophenotypic, and cytogenetic findings in the case of a 39-year-old man with acute megakaryoblasticleukemia (AML-M7).

Cytogenetic analysis revealed two translocations, t(8;17)(q23;q24.2) and t(9;22)(p24.1;q12.2), at presentation; to our knowledge, this combination is a novel finding for acute megakaryoblasticleukemia.

Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblasticleukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation.

The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients.

We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members.

Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression.

Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes.

Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21.

Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Characterization of 6q abnormalities in childhood acutemyeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblasticleukemia.

Chromosome abnormalities of 6q are not frequently observed in myeloid disorders.

In this article, we report the incidence of these chromosome changes in childhood myeloid leukemia as 2%-4% based on the cytogenetic database of a single institution.

We applied fluorescence in situ hybridization (FISH) to characterize precisely the types of 6q abnormalities in seven patients (six with acutemyeloid leukemia and one with myelodysplastic syndrome).

Among these, we identified a novel translocation, t(6;11)(q24.1;p15.5), in a patient with acute megakaryoblasticleukemia.

Further studies will aim to fully characterize C6orf80 and will elucidate the role of this new NUP98 fusion in myeloid leukemia.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Some clinical manifestations of acuteleukemia in children can mimic orthopedic conditions, and t is variable presentation often makes diagnosis difficult.

Bone changes in leukemia are well documented, but there are only a few accounts of children with acuteleukemia who present with bone fractures.

This report describes a case of this rare combination in a very young boy who presented with fractures of both proximal humerus and left proximal femur and massive periosteal reactions of both humerus and femur and also cystic lesions of proximal femur and iliac bone accompanying aggressive acute megakaryoblasticleukemia.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Moreover, hematologists have also noted that these children commonly show macrocytosis, abnormal platelet counts, and an increased incidence of transient myeloproliferative disease (TMD), acutemegakaryocytic leukemia (AMKL), and acute lymphoid leukemia (ALL).

In this review, we summarize the clinical manifestations and characteristics of these leukemias, provide an update on therapeutic strategies and patient outcomes, and discuss the most recent advances in DS-leukemia research.

With the increased knowledge of the way in which trisomy 21 affects hematopoiesis and the specific genetic mutations that are found in DS-associated leukemias, we are well on our way toward designing improved strategies for treating both myeloid and lymphoid malignancies in this high-risk population.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Activating mutations in human acute megakaryoblasticleukemia.

To gain insight into the oncogenic process leading to acute megakaryoblasticleukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders.

In a series of human AMKL samples from both Down syndrome and non-Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients.

We experienced three patients with AMKL, one of whom had Down's syndrome, whose blasts at the first visit exhibited both monosomy 7 and a ring/marker chromosome.

While it is not clear whether the ring/marker chromosome 7 affects the long-term prognosis of acutemyeloid leukemia with monosomy 7, it may be of prognostic relevance to distinguish pure monosomy 7 from monosomy 7 with a ring/marker chromosome 7.

These methods may be useful for determining the optimal treatment and for elucidating the etiology of AMKL itself.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The occurrence of MLL gene rearrangement in acute megakaryoblasticleukemia (AML-M7, acutemyeloid leukemia, French-American-British typeM7) is very rare and limited to pediatric age: in particular, MLL-MLLT10 fusion, previously reported as characteristic of monocytic leukemia, has been reported in only one case of pediatric megakaryoblasticleukemia.

We describe the second case with this association in light of the few reported cases of AML-M7 with MLL and/or 11q23 involvement.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Acute megakaryoblasticleukemia (AMKL) is a form of acutemyeloid leukemia (AML) associated with a poor prognosis.

The genetics and pathophysiology of AMKL are not well understood.

We generated a knockin mouse model of the one twenty-two-megakaryocyticacuteleukemia (OTT-MAL) fusion oncogene that results from the t(1;22)(p13;q13) translocation specifically associated with a subtype of pediatric AMKL.

Furthermore, cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL that recapitulated all the features of human AMKL, including megakaryoblast hyperproliferation and maturation block, thrombocytopenia, organomegaly, and extensive fibrosis.

Our results establish that concomitant activation of RBPJ (Notch signaling) and MPL (cytokine signaling) transforms cells of the megakaryocytic lineage and suggest that specific targeting of these pathways could be of therapeutic value for human AMKL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Complex karyotype defined by molecular cytogenetic FISH and M-FISH in an infant with acute megakaryoblasticleukemia and neurofibromatosis.

Acutemyeloid leukemia in childhood is a heterogeneous group of diseases, and different epidemiologic factors are involved in the etiopathogenesis.

Genetic syndromes are one of the predisposing factors of acutemyeloid leukemia (AML), including Down syndrome, Bloom syndrome, and neurofibromatosis.

Acute megakaryoblasticleukemia (AMKL) is the main subtype in Down syndrome infants, and acquired chromosomal anomalies are closely related to the physiopathology of the illness.

The main chromosomal anomalies in AMKL are structural, such as t(1;22); however, complex karyotypes are also common.

Here we describe the case of an infant with neurofibromatosis developing AMKL with a complex karyotype including 5q and 17q deletions, TP53 deletion, and an unusual unbalanced chromosomal translocation t(11;19)(q13;p13), leading to three copies of the MLL gene.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A novel mutation in the GATA1 gene associated with acute megakaryoblasticleukemia in a Korean Down syndrome patient.

Although acquired mutations in the GATA1 gene have been reported for Down syndrome-related acute megakaryoblasticleukemia (DS-AMKL) in Caucasians, this is the first report of a Korean Down syndrome patient with AMKL carrying a novel mutation of the GATA1 gene.

The findings of a peripheral blood smear and bone marrow study were compatible with the presence of AMKL.

This case demonstrates that a leukemogenic mechanism for DS-AMKL is contributed by a unique collaboration between overexpressed genes from trisomy 21 and an acquired GATA1 mutation previously seen in Caucasians and now in a Korean patient.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Transient leukemia in newborns with Down syndrome.

Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing leukemia, particularly acutemegakaryocytic leukemia.

Newborns with DS or trisomy 21 mosaicism may exhibit a particularly unique form of leukemia that historically has been associated with a high rate of spontaneous remission.

This transient leukemia (TL) has been shown to be a clonal proliferation of blast cells exhibiting megakaryocytic features.

At presentation, many infants are clinically well with only an incidental finding of abnormal blood counts and circulating blasts in the peripheral blood.

However, in approximately 20% of cases, the disease is severe and life-threatening, manifesting as hydrops faetalis, multiple effusions, and liver or multi-organ system failure resulting in death.

Of those children who enter a spontaneous remission, 13-33% have been found to develop subsequent acute megakaryoblasticleukemia, usually within the first 3 years of life, which if left untreated is fatal.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

DS children have a approximately 10- to 20-fold higher risk for developing acute lymphoblastic leukemia and acutemyeloid leukemia (AML), as compared with non-DS children, although they do not have a uniformly increased risk of developing solid tumors.

DS children also develop AML with unique features and have a 500-fold increased risk of developing the AML subtype, acutemegakaryocytic leukemia (AMkL; M7).

Nearly 10% of DS newborns are diagnosed with a variant of AMkL, the transient myeloproliferative disorder, which can resolve spontaneously without treatment; event-free survival rates for DS patients with AMkL ranges from 80% to 100%, in comparison with <30% for non-DS children with AMkL.

In addition, somatic mutations of the GATA1 gene have been detected in nearly all DS TMD and AMkL cases and not in leukemia cases in non-DS children.

GATA1 mutations are key factors linked to both leukemogenesis and the high cure rates of DS AMkL patients.

Identifying the mechanisms that account for the high event-free survival rates of DS AMkL patients may ultimately improve AML treatment as well.

Examining leukemogenesis in DS children may identify factors linked to the general development of childhood leukemia and lead to potential new therapeutic strategies to fight this disease.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Increased erythrocyte mean corpuscular volume (MCV) is frequently found among DS infants and remains elevated throughout life in two-thirds of patients, making interpretation of red cell indices for diagnosis of nutritional anemias or bone marrow failure disorders more challenging.

Transient myeloproliferative disorder (TMD) associated with pancytopenia, hepatosplenomegaly, and circulating immature WBCs, is found almost exclusively in DS infants with an incidence of approximately 10%.

Despite the high rate of spontaneous regression, TMD can be a preleukemic disorder in 20-30% of children with DS.

There is an increased risk of leukemia with an equal incidence of lymphoid and myeloid leukemia.

Acutemegakaryocytic leukemia (AMKL) subtype is the most common form of acutemyeloid leukemia (AML) in this setting, and is uncommon in children without DS.

Somatic mutations of the gene encoding the hematopoetic growth factor GATA1 have been shown to be specific for TMD and AMKL in children with DS.

Children with DS and leukemia are more sensitive to some chemotherapeutic agents such as methotrexate than other children which requires careful monitoring for toxicity.

Although the risk for leukemia is higher in individuals with DS, these patients have a lower risk of developing solid tumors, with the exception of germ cell tumors, and perhaps retinoblastoma and lymphoma.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Down syndrome (DS) children have a unique genetic susceptibility to develop leukemia, in particular, acutemegakaryocytic leukemia (AMkL) associated with somatic GATA1 mutations.

The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of leukemia in children overall.

On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise.

Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop leukemia.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

OTT1(RBM15) was originally described as a 5' translocation partner of the MAL(MKL1) gene in t(1,22)(p13;q13) infant acute mega karyocytic leukemia.

To define the role of OTT1 in hematopoiesis and help elucidate the mechanism of t(1,22) acutemegakaryocytic leukemia pathogenesis, a conditional allele of Ott1 was generated in mice.

There is myeloid and megakaryocytic expansion in spleen and bone marrow, an increase in the Lin(-)Sca-1(+)c-Kit(+) compartment that includes hematopoietic stem cells, and a shift in progenitor fate toward granulocyte differentiation.

These data show a requirement for Ott1 in B lymphopoiesis, and inhibitory roles in the myeloid, megakaryocytic, and progenitor compartments.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Dynamic changes in neuronal morphology and transcriptional regulation play crucial roles in the neuronal network and function.

Accumulating evidence suggests that the megakaryoblasticleukemia (MKL) family members, which function not only as actin-binding proteins but also as serum response factor (SRF) transcriptional coactivators, regulate neuronal morphology.

However, the extracellular ligands and signaling pathways, which activate MKL-mediated morphological changes in neurons, remain unresolved.

In contrast, activin promoted the nuclear export of suppressor of cancer cell invasion (SCAI), which is a corepressor for SRF and MKL.

Collectively, these results strongly suggest that activin-SCAI-MKL signaling is a novel pathway that regulates the dendritic morphology of rat cortical neurons by excluding SCAI from the nucleus and activating MKL/SRF-mediated gene expression.

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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Children with Down syndrome (DS) have a marked increase in susceptibility to Acute Megakaryoblastic Leukaemia (DS-AMKL) and the closely linked neonatal preleukaemic syndrome, Transient Myeloproliferative Disorder (DS-TMD).

The distinct stages of DS-TMD and DS-AMKL provide an excellent tractable model to study leukaemogenesis.

This review focuses on recent studies describing clinical, haematological and biological features of DS-AMKL and DS-TMD.

The findings from these studies suggest that mutations in the key haemopoietic regulator GATA1 (GATA binding protein 1) in DS-AMKL and DS-TMD may be useful in diagnosis and assessing minimal residual disease.

These findings raise the possibility of population-based screening strategies for DS-TMD and the development of treatment to eliminate the preleukaemic TMD clone to prevent DS-AMKL.

These findings have implications for leukaemia biology more broadly given the frequency of acquired trisomy in other human leukaemias.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblasticleukemia in a murine bone marrow transplantation model.

Acute megakaryoblasticleukemia (AMKL) is a subtype of acutemyeloid leukemia associated with a poor prognosis.

However, there are relatively few insights into the genetic etiology of AMKL.

We developed a screening assay for mutations that cause AMKL, based on the hypothesis that constitutive activation of STAT5 would be a biochemical indicator of mutation in an upstream effector tyrosine kinase.

We screened human AMKL cell lines for constitutive STAT5 activation, and then used an approach combining mass spectrometry identification of tyrosine phosphorylated proteins and growth inhibition in the presence of selective small molecule tyrosine kinase inhibitors that would inform DNA sequence analysis of candidate tyrosine kinases.

Using this strategy, we identified a new JAK2T875N mutation in the AMKL cell line CHRF-288-11.

In a murine transplant model, JAK2T875N induced a myeloproliferative disease characterized by features of AMKL, including megakaryocytic hyperplasia in the spleen; impaired megakaryocyte polyploidization; and increased reticulin fibrosis of the bone marrow and spleen.

These findings provide new insights into pathways and therapeutic targets that contribute to the pathogenesis of AMKL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

We report the case of a 4-week-old infant diagnosed with acute megakaryoblasticleukemia with the t (1;22) (p13, q13) who presented with ascites caused by massive infiltration of hepatic sinusoids by leukemic cells.

Marrow fibrosis appeared after infiltrative disease in the liver and liver fibrosis.

We describe the microscopic liver findings and associated clinical presentation that, in the absence of bone marrow involvement, can be difficult to diagnose as leukemia.

Few cases have been reported in the medical literature with the liver as the primary site of involvement in congenital leukemia.

Awareness of this unusual clinical presentation and of the characteristic liver pathology may facilitate the pathologic diagnosis.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Down myeloid disorders: a paradigm for childhood preleukaemia and leukaemia and insights into normal megakaryopoiesis.

Newborns and children with Down Syndrome are predisposed to a range of blood disorders, which include acute lymphoblastic leukaemia and acutemegakaryocyticleukaemia (AMKL).

Over the last four years there has been considerable progress in our understanding of DS AMKL.

Like other childhood leukaemias DS AMKL is initiated in utero and can present in the neonatal period as a clinically overt preleukaemic condition, transient myeloproliferative disorder (TMD).

In approximately 30% of TMD patients, additional as yet unidentified (epi)genetic mutations are required for progression to AMKL.

Thus, DS TMD and AMKL provide a unique model of childhood leukaemia where the preleukaemic and leukaemic phases are ascertainable and separable allowing distinct steps in leukaemogenesis to be studied individually.

These findings also have implications for the clinical management of DS TMD and AMKL specifically and also of childhood leukaemia more generally.

[Number-of-references] 23

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Patients with Down syndrome (DS) display a unique spectrum of malignancies, with a 10- to 20-fold higher risk of acuteleukemias, and a markedly lower incidence of solid tumors.

This review discusses the current understanding of the basis for this distinctive pattern of cancer incidence and the clinical and biologic features of the malignant disorders most frequent in DS individuals: transient myeloproliferative disease, acute megakaryoblasticleukemia, and acute lymphoblastic leukemia.

We also review distinctive pharmacogenetic issues, highlighting the differential chemosensitivity and toxicity profiles of DS patients compared with the general population, and epidemiologic studies of protective and adverse environmental risk factors for the development of leukemia.

[Publication-country] United States

[Other-IDs] NLM/ PMC2709665

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] GATA1-related leukaemias.

GATA1 is a prototypical lineage-restricted transcription factor that is central to the correct differentiation, proliferation and apoptosis of erythroid and megakaryocytic cells.

Mutations in GATA1 can generate a truncated protein, which contributes to the genesis of transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukaemia (AMKL) in infants with Down syndrome.

Similarly, Gata1 knockdown to 5% of its wild-type level causes high incidence of erythroid leukaemia in mice.

The GATA1-related leukaemias in both human and mouse could provide important insights into the mechanism of multi-step leukaemogenesis.

Efforts are afoot to produce mouse models that are reflective of TMD and AMKL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Intense myelofibrosis is rarely associated with de novo acutemyeloidleukaemia (AML) except in acute megakaryoblastic leukaemia (AML-M7) where there is diffuse marrow fibrosis as a consequence of proliferation of neoplastic myeloid cells.

AML associated with significant myelofibrosis developing both de novo or secondary to primary (idiopathic) myelofibrosis is characterised by a fulminant course and extremely poor prognosis, primarily due to treatment-resistant disease.

The prognostic value of degree of marrow fibrosis in de novo AML has been poorly investigated.

We describe a case of extensive myelofibrosis associated with acute erythroblastic leukaemia (AML-M6) that responded to induction therapy of the leukaemia.

[Title] GATA1 mutation and trisomy 21 are required only in haematopoietic cells for development of transient myeloproliferative disorder.

We previously reported two rare neonates without DS who had TMD, one of whom progressed to AMKL.

Trisomy 21 was detected only in blood cells at presentation with TMD/AMKL and disappeared with disease resolution.

We now show that the blood cells at presentation of TMD harboured GATA1 genomic DNA mutations, suggesting a requirement for trisomy 21 in haematopoietic cells, rather than other cell types, for development of TMD/AMKL.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Down syndrome (DS) patients are frequently complicated with infections, autoimmune phenomena and hematological disorders, including transient abnormal myelopoiesis (TAM) in infancy and acute megakaryoblastic leukaemia (AMKL) in later life.

In this study, serum levels of cytokines from 23 TAM and 15 AMKL patients were examined using the highly sensitive microsphere fluorescence system.

Moreover, abnormal inflammatory cytokinemia was also found in myelodysplastic syndrome (MDS) and AMKL with DS.

These abnormal cytokinemia may have a role in the pathophysiology of TAM, MDS and AMKL in DS, especially in liver fibrosis or myelofibrosis.

TMD and DS-AMKL almost always carry an acquired mutation in GATA1 resulting in exclusive synthesis of a truncated protein (GATA1s), suggesting that both trisomy 21 and GATA1 mutations are required for leukemogenesis.

We show that although Tc1 mice do not develop leukemia, they have macrocytic anemia and increased extramedullary hematopoiesis.

Introduction of GATA1s into Tc1 mice resulted in a synergistic increase in megakaryopoiesis, but did not result in leukemia or a TMD-like phenotype, demonstrating that GATA1s and trisomy of approximately 80% of Hsa21 perturb megakaryopoiesis but are insufficient to induce leukemia.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Expressed throughout the central nervous system, the myocardin-related, megakaryoblastic acuteleukemia 1 and 2 (Mkl1/2) are transcriptional cofactors that can be found tethered in the cytoplasm to monomeric actin but on synaptic activation translocate to the nucleus and associate with transcription factors such as serum response factor (SRF) to regulate expression of structural genes.

Moreover, using the passive avoidance-conditioning paradigm, we identify learning-associated alterations of neuronal Mkl expression that appear to contribute to 2 phases of gene regulation during memory consolidation in the hippocampus.

The second transcriptional phase occurs later at the 3-h postavoidance time point when Mkl accumulates in the nucleus of hippocampal neurons and there is enhanced transcription of Mkl-dependent structural genes that may contribute to the elaboration of new, memory-associated synapses known to appear over the subsequent 3-h period.

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